Ad5/48 hexon oncolytic virus expressing sTGFβRIIFc produces reduced hepatic and systemic toxicities and inhibits prostate cancer bone metastases

Weidong Xu, Zhenwei Zhang, Yuefeng Yang, Zebin Hu, Chi Hsiung Wang, Melanie Morgan, Ying Wu, Ryan Hutten, Xianghui Xiao, Stuart R Stock, Theresa Guise, Bellur S. Prabhakar, Charles Brendler, Prem Seth*

*Corresponding author for this work

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

We are interested in developing oncolytic adenoviruses for the treatment of prostate cancer (PCa) bone metastases. A key limitation of Adenovirus 5 (Ad5) is that upon systemic administration, it produces major liver and systemic toxicities. To address this issue, a chimaeric Ad5/48 adenovirus mHAd.sTβRFc was created. Seven hypervariable regions of Ad5 hexon present in Ad5-based Ad.sTβRFc expressing soluble transforming growth factor beta receptorII-Fc fusion protein (sTGβRIIFc), were replaced by those of Ad48. mHAd.sTβRFc, like Ad.sTβRFc, was replication competent in the human PCa cells, and produced high levels of sTGβRIIFc expression. Compared to Ad.sTβRFc, the systemic delivery of mHAd.sTβRFc in nude mice resulted in much reduced systemic toxicity, and reduced liver sequestration. Ad.sTβRFc produced significant liver necrosis, and increases in alanine transaminase, aspartate transaminase, lactate dehydrogenase, tumor necrosis factor-α, and interleukin-6 levels, while mHAd.sTβRFc produced much reduced responses of these markers. Intravenous delivery of Ad.sTβRFc or mHAd.sTβRFc (5 × 10 10 viral particles/mouse) in nude mice bearing PC-3-luc PCa bone metastases produced inhibition of bone metastases. Moreover, a larger dose of the mHAd.sTβRFc (4 × 10 11 viral particles /mouse) was also effective in inhibiting bone metastases. Thus, mHAd.sTβRFc could be developed for the treatment of PCa bone metastases.

Original languageEnglish (US)
Pages (from-to)1504-1517
Number of pages14
JournalMolecular Therapy
Volume22
Issue number8
DOIs
StatePublished - Jan 1 2014

Fingerprint

Oncolytic Viruses
Bone Neoplasms
Adenoviridae
Prostatic Neoplasms
Neoplasm Metastasis
Liver
Nude Mice
Transforming Growth Factor beta
Virion
Bone and Bones
Aspartate Aminotransferases
Alanine Transaminase
L-Lactate Dehydrogenase
Interleukin-6
Proteins
Necrosis
Tumor Necrosis Factor-alpha

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Xu, Weidong ; Zhang, Zhenwei ; Yang, Yuefeng ; Hu, Zebin ; Wang, Chi Hsiung ; Morgan, Melanie ; Wu, Ying ; Hutten, Ryan ; Xiao, Xianghui ; Stock, Stuart R ; Guise, Theresa ; Prabhakar, Bellur S. ; Brendler, Charles ; Seth, Prem. / Ad5/48 hexon oncolytic virus expressing sTGFβRIIFc produces reduced hepatic and systemic toxicities and inhibits prostate cancer bone metastases. In: Molecular Therapy. 2014 ; Vol. 22, No. 8. pp. 1504-1517.
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abstract = "We are interested in developing oncolytic adenoviruses for the treatment of prostate cancer (PCa) bone metastases. A key limitation of Adenovirus 5 (Ad5) is that upon systemic administration, it produces major liver and systemic toxicities. To address this issue, a chimaeric Ad5/48 adenovirus mHAd.sTβRFc was created. Seven hypervariable regions of Ad5 hexon present in Ad5-based Ad.sTβRFc expressing soluble transforming growth factor beta receptorII-Fc fusion protein (sTGβRIIFc), were replaced by those of Ad48. mHAd.sTβRFc, like Ad.sTβRFc, was replication competent in the human PCa cells, and produced high levels of sTGβRIIFc expression. Compared to Ad.sTβRFc, the systemic delivery of mHAd.sTβRFc in nude mice resulted in much reduced systemic toxicity, and reduced liver sequestration. Ad.sTβRFc produced significant liver necrosis, and increases in alanine transaminase, aspartate transaminase, lactate dehydrogenase, tumor necrosis factor-α, and interleukin-6 levels, while mHAd.sTβRFc produced much reduced responses of these markers. Intravenous delivery of Ad.sTβRFc or mHAd.sTβRFc (5 × 10 10 viral particles/mouse) in nude mice bearing PC-3-luc PCa bone metastases produced inhibition of bone metastases. Moreover, a larger dose of the mHAd.sTβRFc (4 × 10 11 viral particles /mouse) was also effective in inhibiting bone metastases. Thus, mHAd.sTβRFc could be developed for the treatment of PCa bone metastases.",
author = "Weidong Xu and Zhenwei Zhang and Yuefeng Yang and Zebin Hu and Wang, {Chi Hsiung} and Melanie Morgan and Ying Wu and Ryan Hutten and Xianghui Xiao and Stock, {Stuart R} and Theresa Guise and Prabhakar, {Bellur S.} and Charles Brendler and Prem Seth",
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Xu, W, Zhang, Z, Yang, Y, Hu, Z, Wang, CH, Morgan, M, Wu, Y, Hutten, R, Xiao, X, Stock, SR, Guise, T, Prabhakar, BS, Brendler, C & Seth, P 2014, 'Ad5/48 hexon oncolytic virus expressing sTGFβRIIFc produces reduced hepatic and systemic toxicities and inhibits prostate cancer bone metastases', Molecular Therapy, vol. 22, no. 8, pp. 1504-1517. https://doi.org/10.1038/mt.2014.80

Ad5/48 hexon oncolytic virus expressing sTGFβRIIFc produces reduced hepatic and systemic toxicities and inhibits prostate cancer bone metastases. / Xu, Weidong; Zhang, Zhenwei; Yang, Yuefeng; Hu, Zebin; Wang, Chi Hsiung; Morgan, Melanie; Wu, Ying; Hutten, Ryan; Xiao, Xianghui; Stock, Stuart R; Guise, Theresa; Prabhakar, Bellur S.; Brendler, Charles; Seth, Prem.

In: Molecular Therapy, Vol. 22, No. 8, 01.01.2014, p. 1504-1517.

Research output: Contribution to journalArticle

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T1 - Ad5/48 hexon oncolytic virus expressing sTGFβRIIFc produces reduced hepatic and systemic toxicities and inhibits prostate cancer bone metastases

AU - Xu, Weidong

AU - Zhang, Zhenwei

AU - Yang, Yuefeng

AU - Hu, Zebin

AU - Wang, Chi Hsiung

AU - Morgan, Melanie

AU - Wu, Ying

AU - Hutten, Ryan

AU - Xiao, Xianghui

AU - Stock, Stuart R

AU - Guise, Theresa

AU - Prabhakar, Bellur S.

AU - Brendler, Charles

AU - Seth, Prem

PY - 2014/1/1

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